Process for the preparation of compounds of the cyclopentanopolyhydrophenanthrene series



Patented May 25, 1954 UNITED STATES PROCESS FOR THE POUNDS OF THEHYDROPHENANTH PREPARATION OF COM- CYCLOPEN TAN OPOLY- RENE SERIES Karllviiescher, Riehen, and Charles Meystre, Basel, Switzerland, assignorsto Ciba Pharmaceutical Products, 1110., Summit, N. J.

No Drawing. Application December 27, 1950, Serial No. 203,021

(llaims priority, application Switzerland November 17, 1948 3 Claims.

This application is a continuation-in-part of our copending applicationSerial No. 126,054, filed on November 7, 1949, now Patent No. 2, 23,885.

The invention relates to the preparation of compounds of thecyclopentanopolyhydrophenanthrene series by reduction of keto groups ofcompounds of the said series with lithium-boron hydride or sodium-boronhydride, in which process a 3-positioned arc-unsaturated keto-groupingpresent is not hydrogenated.

According to the present invention arc-unsaturated 3-ketones of thecyclopentanopolyhydrophenanthrene series are temporarily converted intotheir enol ethers or cyclic acetals for protection of the 3-positionedketo group and treated, for the purpose of reduction of keto groups,with lithium-boron hydride or sodium-boron hydride.

The cup-unsaturated ketones of the cyclopentanopolyhydrophenanthreneseries, which contain as reducible substituents a keto group, may

be converted into any convenient enol ether or cyclic acetal. Suitableenol ethers are those of the aliphatic, alicyclic or araliphatic series;in particular alkyl ethers are employed, as for eX- ample, methyl, ethylor propyl ethers. There may be particularly mentioned the enol ethers ofA -3:17-androstendione. In the manufacture or the cyclic acetals ofthese starting materials, particularly of the ethylene glycol, there areused the 1,2-diols or the corresponding alkylene oxides in the presenceof an acid catalyst.

The reduction is advantageously carried out in the presence of anindiiierent solvent in which the light metal-light metal hydride issoluble, in

particular in the presence of ether, or also of 3 tetrahydrofurane,butyl ether or benzene or of mixtures of such diluents, such as in thepresence of a mixture of ether and benzene. When sodium-boron hydride isused as reducing agent,

it is advantageous to work in the presence of water, using e. g. amixture of methanol, dioxane and water.

The enol ethers or cyclic acetals of hydroxyketones obtained in thecourse of this process can be hydrolyzed in the customary manner inorder A to produce the corresponding ketones.

Some of the ketones obtained merit application as therapeutic media.They may also be employed as intermediate products for the manufactureof therapeutically valuable compounds.

The following examples illustrate the invention, the parts being byweight unless otherwise stated and the relationship between parts byweight and parts by volume being the same as that between the kilogramand liter:

Example 1 2 parts of the 3-ethyl enol ether of A -3zl7- androstendioneare dissolved in 200 parts by volume of dry ether and slowly added, withexclusion of moisture, to a well stirred mixture of .5 part oflithium-boron hydride in 100 parts by volume or" dry ether. The solutionproduced is further stirred for minutes and thereupon carefully treatedwith parts by volume of water and it] parts by volume of 10 per cent.sulfuric acid. The ethereal solution is then washed with water, driedand evaporated. The crude enol ether of A -3-keto-17-hydroxy-androsteneis, without further purification, dissolved in 100 parts by Volume ofalcohol and the solution treated with 10 parts by volume ofZN-hydrochloric acid and allowed to stand for 24 hours. The solution isthereupon evaporated in vacuum and in this manner the crude A-3-keto-17-hydroxy-androstene (testosterone) obtained, which can bepurified in the customary manner. For example, from diluted acetoneneedles are obtained of melting point 152-153 C.

([cz] =+199 in ethanol) Example 2 10 parts of the 3-ethyl enol ether ofA -3zl7- androstendione are dissolved in 220 parts by volume of methanoland slowly added to a well stirred solution of 1.5 parts of sodium-boronhydride in parts by volume of methanol. 'I'hereupon the mixture isrefluxed for hour. parts or" 10 per cent. potassium carbonate are addedand the mixture is stirred and refluxed for 1 hour. Then the mixture ismade acid to Congo red with dilute sulfuric acid and refluxed for 1hour. Methanol is removed completely under reduced pressure. The mixtureis then cooled and crude testosterone filtered, yield 97 per cent. Bycrystallizing this product once from diluted acetone pure testosteroneof melting point 152-153 C. is obtained.

Having thus described the invention, what is claimed is:

1. Process for the reduction Of compounds of thecyclopentanopolyhydrophenanthren series, which comprises treating a A-3-keto compound of the said series, which contain as a furthersubstituent an oxo group, in the form of a member of the groupconsisting of 3-enol-ethers and 3- cyclic acetals, with a. memberselected from the group consisting of lithium-boron hydride andsodium-boron hydride and hydrolyzing the so 4 dride and. hydrolyzing theso formed product, whereby A -3-keto-I'I-hydroxy-androstene is obtained.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,294,433 Westphal Sept. 1, 1942 2,588,294 Rosenkranz Mar, 4,1952 OTHER REFERENCES Chaikin et 9.1., Journal Am. Chem. Soc. 71,122-425 (1949).

1. PROCESS FOR THE REDUCTION OF COMPOUNDS OF THECYCLOPENTANOPOLYHYDROPHENANTHRENE SERIES, WHICH COMPRISES TREATING A$4-3-KETO COMPOUND OF THE SAID SERIES, WHICH CONTAINS AS A FURTHERSUBSTITUENT AN OXO GROUP, IN THE FORM OF A MEMBER OF THE GROUPCONSISTING OF LITHIUM-BORON HYDRIDE AND CYCLIC ACETALS, WITH A MEMBERSELECTED FROM THE GROUP CONSISTING OF LITHIUM-BORON HYDRIDE ANDSODIUM-BORON HYDRIDE AND HYDROLYZING THE SO FORMED REACTION PRODUCTWHEREBY THE $4-3-KETO COMPOUND WITH THE REDUCED FURTHER SUBSTITUENT ISOBTAINED.